Surgery
Treatment Options for Patients With Optimally Cytoreduced Stage III Disease
Treatment Options for Patients With Suboptimally Cytoreduced Stage III and Stage IV Disease
Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Treatment options for patients with all stages of ovarian epithelial cancer have consisted of surgery followed by chemotherapy.

Patients diagnosed with stage III and stage IV disease are treated with surgery and chemotherapy; however, the outcome is generally less favorable for patients with stage IV disease. The role of surgery for patients with stage IV disease is unclear, but in most instances, the bulk of the disease is intra-abdominal, and surgical procedures similar to those used in the management of patients with stage III disease are applied. The options for intraperitoneal (IP) regimens are also less likely to apply both practically (as far as inserting an IP catheter at the outset) and theoretically (aimed at destroying microscopic disease in the peritoneal cavity) in patients with stage IV disease.

Surgery has been used as a therapeutic modality and also to adequately stage the disease. Surgery should include total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy and debulking of as much gross tumor as can safely be performed. While primary cytoreductive surgery may not correct for biologic characteristics of the tumor, considerable evidence indicates that the volume of disease left at the completion of the primary surgical procedure is related to patient survival.[1] A literature review showed that patients with optimal cytoreduction had a median survival of 39 months compared with survival of only 17 months in patients with suboptimal residual disease.[1][Level of evidence: 3iA] Results of a retrospective analysis of 349 patients with postoperative residual masses no larger than 1 cm suggested that patients who present at the outset with large-volume disease and achieve small-volume disease by surgical debulking have poorer outcomes than similar patients who present with small-volume disease.[2] Gradual improvement in survival with decreasing residual tumor volume is likely. Although the association may not be causal, retrospective analyses, including a meta-analysis of patients receiving platinum-based chemotherapy, have found cytoreduction to be an independent prognostic variable for survival.[3,4]

For the past 3 decades, the Gynecologic Oncology Group (GOG) has conducted separate trials for women whose disease has been optimally cytoreduced (most recently defined as ≤1 cm residuum) and for those who had suboptimal cytoreductions (>1 cm residuum). The extent of residual disease following the initial surgery is a determinant of outcome in most series [1-4] and has been used in the design of clinical trials, particularly by the GOG.

On the basis of these findings, the standard treatment approaches are subdivided into:

1. Treatment options for patients with optimally cytoreduced stage III disease.
2. Treatment options for patients with suboptimally cytoreduced stage III and stage IV disease.

Rarely, and mostly because of operative risks, it is preferable to treat patients with several cycles of chemotherapy before interval debulking surgery. The European Organisation for the Research and Treatment of Cancer (EORTC) Gynecological Cancer Group, together with the National Cancer Institute of Canada, has initiated a randomized clinical trial (EORTC-55971) to determine whether neoadjuvant chemotherapy followed by such interval debulking surgery will be as effective as primary debulking surgery in some or all patients with stage IIIC and stage IV disease.

Intraperitoneal chemotherapy

The pharmacologic basis for the delivery of anticancer drugs by the IP route was established in the late 1970s and early 1980s. When several drugs were studied, mostly in the setting of minimal residual disease at reassessment after patients had received their initial chemotherapy, cisplatin alone and in combination received the most attention. Favorable outcomes from IP cisplatin were most often seen when tumors had shown responsiveness to platinums and with small-volume tumors (usually defined as tumors <1 cm).[5] In the 1990s, randomized trials were conducted to evaluate whether the IP route would prove superior to the IV route. IP cisplatin was the common denominator of these randomized trials.

The use of IP cisplatin as part of the initial up-front approach in patients with stage III optimally debulked ovarian cancer is supported principally by the results of three randomized clinical trials (GOG-104, GOG-14, and GOG-172).[6-8] These studies tested the role of IP drugs (IP cisplatin in all three studies and IP paclitaxel in the last study) against the standard IV regimen. In the three studies, superior progression-free survival (PFS) and overall survival (OS) favoring the IP arm was documented. Specifically, the most recent study, GOG-172, resulted in a median survival rate of 66 months for patients on the IP arm versus 50 months for patients who received IV administration of cisplatin and paclitaxel (P = .03).[8][Level of evidence:1iiA] Toxic effects were greater in the IP arm, contributed to in large part by the cisplatin dose per cycle (100 mg/m²) and by sensory neuropathy from the additional IP as well as from the IV administration of paclitaxel. The rate of completion of six cycles of treatment was also less frequent in the IP arm (42% vs. 83%) because of the toxic effects and catheter-related problems.[9] Notwithstanding these problems, IP therapy for patients with optimally debulked ovarian cancer is receiving wider adoption, and efforts are under way by the GOG to examine some modifications of the IP regimen used in GOG-172 to improve its tolerability (e.g., to reduce by at least 25% the total 3-hour amount of cisplatin given; a shift from the less practical 24-hour IV administration of paclitaxel to a 3-hour IV administration). A Cochrane-sponsored meta-analysis of all randomized IP versus IV trials shows a hazard ratio of 0.79 for disease-free survival and 0.79 for OS, favoring the IP arms.[10] In another meta-analysis of seven IP versus IV randomized trials that were conducted by Cancer Care of Ontario, the relative ratio (RR) of progression at 5 years based on the three trials that reported this endpoint was 0.91 (95% confidence interval [CI], 0.85–0.98) and the RR of death at 5 years based on six trials was 0.88 (95% CI, 0.81–0.95).[9]

Cytoreductive surgery

The value of interval cytoreductive surgery has been the subject of two large phase III trials. In the first study, performed by the EORTC, patients subjected to debulking after four cycles of cyclophosphamide and cisplatin (with additional cycles given later) had an improved survival rate compared with patients who completed six cycles of this chemotherapy without surgery.[11][Level of evidence: 1iiB] The GOG-162 trial was designed to answer a very similar question but used the then-standard paclitaxel-plus-cisplatin regimen as the chemotherapy.[12] This trial did not demonstrate any advantage from the use of interval cytoreductive surgery. The divergence of results may be caused by the efficacy of the chemotherapy obscuring any effects of interval cytoreduction, the wider use of maximal surgical effort at the time of diagnosis by U.S. gynecologic oncologists, or unknown factors. Although many patients with stage IV disease also undergo cytoreductive surgery at diagnosis, whether this improves survival has not been established.

Systemic chemotherapy

First-line treatment of ovarian cancer is cisplatin, given intravenously, or its second-generation analog, carboplatin, given either alone or in combination with other drugs. Clinical response rates from these drugs regularly exceed 60%, and median time-to-recurrence usually exceeds 1 year in this subset of suboptimally debulked women. Trials by various cooperative groups in the subsequent 2 decades addressed issues of optimal dose-intensity [13-15] for both cisplatin and carboplatin,[16] schedule, [17] and the equivalent results obtained with either of these platinum drugs, usually in combination with cyclophosphamide.[18] With the introduction of the taxane paclitaxel, two trials confirmed the superiority of cisplatin combined with paclitaxel to the previous standard of cisplatin plus cyclophosphamide; however, two trials that compared the agent with either cisplatin or carboplatin as a single agent failed to confirm such superiority in all outcome parameters (i.e., response, time-to-progression, and survival) (see Table 1).

Nevertheless, for patients with ovarian cancer, the combination of cisplatin or carboplatin and paclitaxel has been used as the initial treatment (defined as induction chemotherapy) for a number of reasons:

1. GOG-132 was regarded by many as showing that sequential treatment of cisplatin and paclitaxel was equivalent to the combination because many patients crossed over before progression; moreover, the cisplatin only arm was more toxic because it utilized a 100 mg/m² dose.
2. The Medical Research Council (MRC-ICON3) study, while having fewer early crossovers, could be interpreted similarly in regard to the impact on survival of sequential treatment.
3. Data from MRC-ICON4 have shown a survival advantage for patients treated with the combination treatment regimen versus those treated with single-agent carboplatin upon recurrence (see Table 2).
4. In past trials, single-agent platinums were not superior to platinum combined with an alkylating agent; therefore, the explanation of a detrimental effect of cyclophosphamide is unlikely.

Since the adoption of the platinum-plus-taxane combination as the standard nearly worldwide, clinical trials have demonstrated:

• Noninferiority for carboplatin plus paclitaxel versus cisplatin plus paclitaxel,[19-21]
• Noninferiority for carboplatin plus paclitaxel versus carboplatin plus docetaxel,[22] and
• No advantage but increased toxic effects by adding epirubicin to the carboplatin plus paclitaxel doublet.[23]

The GOG-initiated (GOG-0182-ICON5) study, with international collaboration and published in abstract form, compared the carboplatin-plus-paclitaxel standard to two carboplatin-containing sequential doublets (one with topotecan and one with gemcitabine) followed by carboplatin plus paclitaxel, and to two triplets including either pegylated liposomal doxorubicin or gemcitabine with the standard doublet. No differences have emerged.[24]

Consolidation and/or maintenance therapy

In an effort to improve on the modest results achieved in suboptimally debulked patients (in contrast to those achieved after optimal cytoreduction and IP therapy), trials of consolidation and/or maintenance therapy have been carried out. Presently, none of the treatments given after the initial induction have been shown to improve survival: IP cisplatin × four cycles [25] or radioimmunoconjugate × one cycle [26] following negative reassessment; or IV topotecan × four cycles.[27] However, the SWOG/GOG study comparing 3 versus 12 doses of monthly paclitaxel given every 4 weeks following a clinically defined complete response at the time of completion of platinum/paclitaxel induction was stopped early because of a very significant difference in PFS.[28][Level of evidence: 1iiDiii] Trials to confirm the value of maintenance with taxanes versus observation are being conducted by the GOG.

Treatment options under clinical evaluation:

• IP radioimmunoconjugates, vaccines, and targeted drugs are under clinical evaluation, primarily as consolidation therapy.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III ovarian epithelial cancer and stage IV ovarian epithelial cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Hoskins WJ: Surgical staging and cytoreductive surgery of epithelial ovarian cancer. Cancer 71 (4 Suppl): 1534-40, 1993.  [PUBMED Abstract]
   
   
2. Hoskins WJ, Bundy BN, Thigpen JT, et al.: The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 47 (2): 159-66, 1992.  [PUBMED Abstract]
   
   
3. Hoskins WJ, McGuire WP, Brady MF, et al.: The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 170 (4): 974-9; discussion 979-80, 1994.  [PUBMED Abstract]
   
   
4. Bristow RE, Tomacruz RS, Armstrong DK, et al.: Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 20 (5): 1248-59, 2002.  [PUBMED Abstract]
   
   
5. Howell SB, Zimm S, Markman M, et al.: Long-term survival of advanced refractory ovarian carcinoma patients with small-volume disease treated with intraperitoneal chemotherapy. J Clin Oncol 5 (10): 1607-12, 1987.  [PUBMED Abstract]
   
   
6. Alberts DS, Liu PY, Hannigan EV, et al.: Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 335 (26): 1950-5, 1996.  [PUBMED Abstract]
   
   
7. Markman M, Bundy BN, Alberts DS, et al.: Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 19 (4): 1001-7, 2001.  [PUBMED Abstract]
   
   
8. Armstrong DK, Bundy B, Wenzel L, et al.: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354 (1): 34-43, 2006.  [PUBMED Abstract]
   
   
9. Elit L, Oliver TK, Covens A, et al.: Intraperitoneal chemotherapy in the first-line treatment of women with stage III epithelial ovarian cancer: a systematic review with metaanalyses. Cancer 109 (4): 692-702, 2007.  [PUBMED Abstract]
   
   
10. Jaaback K, Johnson N: Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev (1): CD005340, 2006.  [PUBMED Abstract]
    
    
11. van der Burg ME, van Lent M, Buyse M, et al.: The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med 332 (10): 629-34, 1995.  [PUBMED Abstract]
    
    
12. Goodman HM, Harlow BL, Sheets EE, et al.: The role of cytoreductive surgery in the management of stage IV epithelial ovarian carcinoma. Gynecol Oncol 46 (3): 367-71, 1992.  [PUBMED Abstract]
    
    
13. Markman M, Reichman B, Hakes T, et al.: Impact on survival of surgically defined favorable responses to salvage intraperitoneal chemotherapy in small-volume residual ovarian cancer. J Clin Oncol 10 (9): 1479-84, 1992.  [PUBMED Abstract]
    
    
14. Markman M: Intraperitoneal chemotherapy. Semin Oncol 18 (3): 248-54, 1991.  [PUBMED Abstract]
    
    
15. Levin L, Simon R, Hryniuk W: Importance of multiagent chemotherapy regimens in ovarian carcinoma: dose intensity analysis. J Natl Cancer Inst 85 (21): 1732-42, 1993.  [PUBMED Abstract]
    
    
16. McGuire WP, Hoskins WJ, Brady MF, et al.: Assessment of dose-intensive therapy in suboptimally debulked ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 13 (7): 1589-99, 1995.  [PUBMED Abstract]
    
    
17. Bolis G, Favalli G, Danese S, et al.: Weekly cisplatin given for 2 months versus cisplatin plus cyclophosphamide given for 5 months after cytoreductive surgery for advanced ovarian cancer. J Clin Oncol 15 (5): 1938-44, 1997.  [PUBMED Abstract]
    
    
18. Alberts DS, Green S, Hannigan EV, et al.: Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer. J Clin Oncol 10 (5): 706-17, 1992.  [PUBMED Abstract]
    
    
19. du Bois A, Lück HJ, Meier W, et al.: A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95 (17): 1320-9, 2003.  [PUBMED Abstract]
    
    
20. Neijt JP, Engelholm SA, Tuxen MK, et al.: Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 18 (17): 3084-92, 2000.  [PUBMED Abstract]
    
    
21. Ozols RF, Bundy BN, Greer BE, et al.: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 21 (17): 3194-200, 2003.  [PUBMED Abstract]
    
    
22. Vasey PA, Jayson GC, Gordon A, et al.: Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst 96 (22): 1682-91, 2004.  [PUBMED Abstract]
    
    
23. Kristensen GB, Vergote I, Stuart G, et al.: First-line treatment of ovarian cancer FIGO stages IIb-IV with paclitaxel/epirubicin/carboplatin versus paclitaxel/carboplatin. Int J Gynecol Cancer 13 (Suppl 2): 172-7, 2003 Nov-Dec.  [PUBMED Abstract]
    
    
24. Bookman MA: GOGO182-ICON5: 5-arm phase III randomized trial of paclitaxel and carboplatin vs combinations with gemcitabine, PEG-lipososomal doxorubicin, or topotecan in patients with advanced-stage epithelial ovarian or primary peritoneal carcinoma. [Abstract] J Clin Oncol 24 (Suppl 18): A-5002, 256s, 2006. 
    
    
25. Piccart MJ, Bertelsen K, James K, et al.: Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 92 (9): 699-708, 2000.  [PUBMED Abstract]
    
    
26. Verheijen RH, Massuger LF, Benigno BB, et al.: Phase III trial of intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody in patients with epithelial ovarian cancer after a surgically defined complete remission. J Clin Oncol 24 (4): 571-8, 2006.  [PUBMED Abstract]
    
    
27. Pfisterer J, Weber B, Reuss A, et al.: Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a gynecologic cancer intergroup trial of the AGO-OVAR and GINECO. J Natl Cancer Inst 98 (15): 1036-45, 2006.  [PUBMED Abstract]
    
    
28. Markman M, Liu PY, Wilczynski S, et al.: Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 21 (13): 2460-5, 2003.  [PUBMED Abstract]
    
    

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